Abstract

Continuous contact with self-major histocompatibility complex ligands is essential for the survival of naive CD4 T cells. We have previously shown that the resulting tonic TCR signaling also influences their fate upon activation by increasing their ability to differentiate into induced/peripheral regulatory T cells. To decipher the molecular mechanisms governing this process, we here focus on the TCR signaling cascade and demonstrate that a rise in intracellular calcium levels is sufficient to modulate the phenotype of mouse naive CD4 T cells and to increase their sensitivity to regulatory T-cell polarization signals, both processes relying on Calcineurin activation. Accordingly, in vivo Calcineurin inhibition leads the most Self-reactive naive CD4 T cells to adopt the phenotype of their less Self-reactive cell-counterparts. Collectively, our findings demonstrate that calcium-mediated activation of the Calcineurin pathway acts as a rheostat to shape both the phenotype and effector potential of naive CD4 T cells in the steady-state.

Institut National de la Santé et de la Recherche Médicale

Agence Nationale de la Recherche (ANR-15-CE15-0009-01)

Fondation pour la Recherche Médicale

Bruno Lucas

Ligue Contre le Cancer

Alexandra Audemard-Verger

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Ethics

Animal experimentation: Experiments were carried out in accordance with the guidelines of the French Veterinary Department. All procedures performed were approved by the Paris-Descartes Ethical Committee for Animal Experimentation (decision CEEA34.CA.080.12). Sample sizes were chosen to ensure the reproducibility of the experiments and according to the 3Rs of animal ethics regulation.

Reviewing Editor

Michael L Dustin, Reviewing Editor, University of Oxford, United Kingdom

Further reading

Ca2+ influx through Orai1 channels is crucial for several T cell functions, but a role in regulating basal cellular motility has not been described. Here, we show that inhibition of Orai1 channel activity increases average cell velocities by reducing the frequency of pauses in human T cells migrating through confined spaces, even in the absence of extrinsic cell contacts or antigen recognition. Utilizing a novel ratiometric genetically encoded cytosolic Ca2+ indicator, Salsa6f, which permits real-time monitoring of cytosolic Ca2+ along with cell motility, we show that spontaneous pauses during T cell motility in vitro and in vivo coincide with episodes of cytosolic Ca2+ signaling. Furthermore, lymph node T cells exhibited two types of spontaneous Ca2+ transients: short-duration ‘sparkles’ and longer duration global signals. Our results demonstrate that spontaneous and self-peptide MHC-dependent activation of Orai1 ensures random walk behavior in T cells to optimize immune surveillance.

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